The overall purpose of this proposal is to determine the cellular mechanisms responsible for the cardiac and vascular toxicity of cocaine, the nature of coexisting conditions which can predispose users to toxicity, and approaches for preventing and treating the cardiovascular complications of cocaine exposure. First, we will test the hypothesis that the acute cardiovascular toxicity of cocaine is caused by abnormal intracellular calcium ((Ca++)i) handling and production of a (Ca++)i overload state. Electrical and mechanical studies will be performed with cardiac and vascular tissue from swine and ferrets that has been loaded with the calcium indicator aequorin to directly measure intracellular levels of free, ionized Ca++. Second, we will determine how chronic treatment with cocaine modifies its acute cardiac and vascular effects. Third, we will determine the degree to which the cardiovascular effects and toxicity of cocaine are caused by indirect actions of the drug; in particular, blockage of catecholamine uptake by the adrenergic nerve endings. Studies will be performed before and after the addition of propranolol and phentolamine to block post - synaptic adrenoceptors, nortriptyline to block adrenergic neuronal UPTAKE I mechanisms, or reserpine, to deplete adrenergic neurons of catecholamines. Fourth, we will determine the degree to which the cardiovascular effects and toxicity of cocaine are due to its direct effects on muscle, including actions on the sarcolemma (i.e., local anesthetic, calcium channel blockade, effects on Na+/Ca++ exchange), sarcoplasmic reticulum (i.e., Ca++ uptake and release processes) and myofilaments (i.e., altered Ca++ sensitivity and cross-bridge cycling rates). Fifth, we will identify factors that predispose to, and prevent or reverse, cocaine's cardiovascular toxicity. Experiments will be designed to identify factors that may predispose (i.e., hypertrophy, atherosclerosis, sex, aging, exercise training, hypoxia, body temperature, caffeine, alcohol, nicotine, tyramine) and that may prevent or reverse (i.e., blockade of neuronal uptake of cocaine, adrenergic neuron blockade, alpha and beta adrenoceptor blockade, calcium channel blockade) cocaine's toxicity. Sixth, we will evaluate the toxic effects of cocaine on human cardiac and vascular smooth muscle isolated from patients undergoing cardiac surgery, cardiac transplantation or organ donation. We anticipate that the results of these studies will not only clarify the pathophysiologic basis of cocaine's cardiovascular toxicity but will provide a rational basis for preventative measures and therapeutic interventions.